Fact Sheet on Xenotransplantation

September 20, 1996

Background

Limited availability of human organs and tissues, coupled with recent biotechnical
advances, has increasingly led to implantations of living cells from other species when
human donors are not available, when a bridge organ is needed, or when animal cells may
provide a unique benefit. This is called xenotransplantation.

Between 1990 and 1995, an average of 4,835 people each year donated organs after death,
according to the Health Resources and Services Administration, the federal agency that
oversees the national organ and bone marrow transplantation programs. Nonetheless,
approximately 48,000 people are now on the waiting list for organs, and the number of
individuals awaiting transplants continues to grow. For example, more than 33,000 patients
were awaiting kidney transplants in August 1996. Approximately 3,000 people die each year
because donor organs are not available to them.

The draft Public Health Service guideline was prepared to help minimize public health
risks associated with xenotransplantation while not restricting access to promising
therapies for individuals with life-threatening and chronic debilitating illnesses. The
guideline applies to all types of xenotransplants, including cells, tissues and solid
organs.

Concerns about potential infection with both recognized disease agents and new ones
arising from xenotransplants are real. For example, an infecting microbe may change when
it is transmitted from its natural host into a new species. A virus that does not cause
disease in its animal host may cause serious disease or even be fatal to a human
transplant recipient.

Protecting Public Health: The Draft Guideline for
Xenotransplantation

1. The Clinical Plan

The transplant team should include individuals such as the surgeon, infectious disease
physician, veterinarian, transplant immunologist, infection control specialist, and
clinical microbiologist.

The clinical center should be associated with an accredited virology and microbiology
laboratory.

The protocol should be reviewed by the clinical center Biosafety Committee,
Institutional Animal Care and Use Committee, and the Institutional Review Board. Protocols
are subject to review and approval by FDA.

The protocol should describe the screening methods for known infectious agents before
transplantation.

The informed consent process should include disclosure of the potential risks to the
recipient, the family, or close contacts (especially sexual), and the need to archive pre-
and post-transplant serum specimens for long-term follow-up.

2. Animal Sources

Animals should be procured from screened, closed herds or colonies that are
well-characterized and as free as possible of infectious agents.

Animals should have documented lineages and be bred and reared in captivity.

Other outlined issues address the animal facility, including record-keeping, screening
for known infectious agents, animal qualifications, and archiving of animal medical
records and specimens.

3. Clinical Issues

The health status of xenotransplant recipients should be monitored clinically and
through laboratory tests.

Laboratory testing methods should be established and documented before the transplant is
performed.

Recipients should be educated concerning potential infectious disease risks to
themselves and to their close contacts.

Hospital infection control procedures should be in place.

Laboratories should be available to culture and identify both known and novel infectious
agents.

The health-care team should be educated about the possible infectious disease risks.

Serological samples should be archived for retrospective investigation of possible
infections.

Health-care records should be systematically maintained in ways that protect patients'
confidentiality.

4. Public Health Needs

A national registry is recommended to provide information to assess long-term safety and
to help in epidemiological investigations. FDA, the Centers for Disease Control and
Prevention, and the National Institutes of Health are collaborating with the Health
Resources and Services Administration to develop a pilot program to define the scope,
focus, and optimal design of a national registry. Such a registry would help to identify
xenotransplant-associated health problems that have public health significance.

FDA's Role

The infectious disease risks inherent in all forms of xenotransplantation warrant a
consistent regulatory framework. FDA soon will publish a draft guidance document to
provide further practical information to the transplant community.

FDA regulates numerous products intended to prevent, treat or diagnose diseases or
injuries under the authority of the Public Health Service Act and the Federal Food, Drug,
and Cosmetic Act. Clinical studies of new experimental biologics, such as xenogeneic
cells, tissues and organs, should be performed under an Investigational New Drug (IND)
application that is filed with FDA. IND applications should contain information on product
manufacturing and testing to ensure that trial subjects will not be exposed to
unreasonable risks, taking into account the potential for benefit.

Critical Events Leading to the Guideline

Nov. 17, 1994:

Philip R. Lee, M.D., the assistant secretary for health,
requested that FDA, NIH and CDC hold a consensus conference on infectious disease risks
associated with xenotransplantation. At about the same time, several institutional review
boards contacted FDA regarding proposed xenotransplant studies at their institutions,
expressing concern about the safety of donor animal tissues. A meeting was planned for
early 1995 to discuss the need for specific guidelines.

January 1995: CDC, FDA, NIH, HRSA, the Department of Defense, academic
institutional review boards, animal-care committees, transplant surgeons, the National
Organization of Rare Diseases, and the National Academy of Sciences Institute of Medicine
met to discuss public health concerns regarding xenotransplantation. It was decided that a
comprehensive guideline was needed. Several working groups were formed to discuss what key
elements needed to be included in the guideline.

April 1995: At FDA's Biological Response Modifiers Advisory Committee,
infectious disease issues were discussed. Here also, a sponsor of a xenotransplant
experiment described one approach to controlling infectious disease risks. The committee
outlined preliminary public health safety concerns that should be included in any
guideline for xenotransplantation.

June 25-27, 1995: The Institute of Medicine (IOM) held a public
workshop on scientific, medical, public health, socioeconomic, legal, and ethical issues.
The Public Health Service agencies brought the issue of infectious disease risks to the
workshop for further public discussion and comment.

June 28, 1995: A day later, PHS held a "Federal Day"
workshop to bring the PHS working groups together to discuss their progress on the
guidelines and to create a guideline that would address the issues presented at the IOM
meeting. The goal set was to create a draft guideline for discussion by July 1995.

On July 14, the committee discussed a highly publicized experimental protocol that had
been submitted to the agency for review--a baboon bone marrow transplant to treat a
patient with AIDS. The committee recognized the need for well-designed protocols to
control infectious disease risks. Although questions were asked about the outcome of the
experiment, from the perspective of both the patient and the public health, the committee
recommended that this protocol be approved for one patient. The committee also discussed
extracorporeal liver-assist devices, which may contain live animal cells such as pig liver
cells.

Nov. 30, 1995 New England Journal of Medicine: Sounding Board article
"Xenotransplantation and Xenogeneic Infections" discussed the potential risks
for transplant recipients and to the public health. Written by Drs. Chapman and Folks
(CDC), Dr. Salomon (Scripps Research Institute), and Drs. Patterson, Eggerman and Noguchi
(FDA), the article clarifies the reasons why guidance is needed in the field of
xenotransplantation.

March 1996: PHS met with representatives of the American Society of
Transplant Surgeons and the American Society of Transplant Physicians to discuss
principles of the draft guideline and the perspectives of the transplant community. The
transplant surgeons recommended that FDA, CDC and NIH collaborate with HRSA in
establishing a national registry, since that agency currently oversees the Scientific
Registry of Transplant Recipients.

April 1996: The British Nuffield Council on Bioethics published a
study calling for national regulation of xenotransplantation to be in place before any
clinical trials could proceed.

July 1996: A request for proposals was published for a pilot study of
the National Xenotransplantation Registry operated under contract by HRSA.

July 1996: The Institute of Medicine issued a report on
xenotransplantation calling for national guidelines. Both the IOM and Nuffield
reports supported the concept of a national registry as proposed by PHS.

September 1996: The draft PHS guideline for xenotransplantation is
published.

Public Information About
Phase One (Safety) Clinical Trials Involving Xenotransplantation